Compounds that participate in cooperative binding and uses thereof

Abstract

The invention features compounds (e.g., macrocyclic compounds) capable of modulating biological processes, for example through binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein). These compounds bind endogenous intracellular presenter proteins, such as the FKBPs or cyclophilins, and the resulting binary complexes selectively bind and modulate the activity of intracellular target proteins. Formation of a tripartite complex among the presenter protein, the compound, and the target protein is driven by both protein-compound and protein-protein interactions, and both are required for modulation of the targeted protein's activity.

Description

Background technique

[0001] The vast majority of small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating the activity of said proteins. For example, the cholesterol-lowering drugs statins bind to the enzymatic active site of HMG-CoA reductase, preventing the enzyme from binding to its substrate. The fact that many such drug / target interaction pairs are known may lead some to believe that small molecule modulators can be discovered for most, if not all, proteins given a reasonable amount of time, effort and resources. But in fact, it's not. Current estimates suggest that only about 10% of all human proteins can be targeted by small molecules. The other 90% is currently considered insurmountable or tricky for small molecule drug discovery. Such targets are often referred to as "undruggable". These undruggable targets include a large and largely untapped repertoire of medically important human proteins. Therefore, there i...

Images